Essential Hypertension in Children: New Mechanistic Insights

Paediatric hypertension is on the rise accompanied by concomitant increase of childhood obesity. The origin of paediatric hypertension however remains unknown. New epidemiological evidence suggests that environmental insult in utero or postnatally may lead to hypertension later in life. Independent associations have been reported between maternal obesity and cardiometabolic disorders in the offspring. In the first part, I will focus on functionally mechanistic pathways of essential hypertension with an attempt to elucidate the rather complex interplay of autonomic dysfunction, leptin, melanocortin-4 receptor (MC4R), inflammation, genetic and epigenetic predispositions. In the second part, the standalone risk factors will be integrated in a flow chart in attempt to understand the deeper meaning of this regulatory machinery in paediatric hypertension. I will refer to the pathophysiology of early sympathetic-mediated hypertension arising from maternal obesity. Maternal diet-induced obesity in rodents permanently resets the responsiveness to leptin-induced SNS in rat offspring via the hypothalamic paraventricular nucleus (PVN)-MC4R pathway. The stimulus that mediates Leptin-SNS-MC4R activity and promotes hypertension is still unknown and remains as a key for future investigations. Future research needs to identify effective preventive measures in the pregnant mother and child to reduce the risk of paediatric hypertension and prevent future cardiovascular disease

Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System

Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system

Maternal Obesity Induced by Diet in Rats Permanently Influences Central Processes Regulating Food Intake in Offspring

Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats

Творческий подход студентов в изучении гистологии

Denna rapport innehåller texter som presenterats vid en konferens arrangerad inom ramen för Nätverk för barnomsorgsforskningi . Syftet med konferensen var att lyfta upp begreppet omsorg, diskutera dess innebörd, rädda det från retorisk förflackning och samtidigt via dess koppling till verksamheter belysa ett vidare sammanhang. När bamforskning diskuteras har jag på senare tid funnit det väsentligt att peka på att den har en kapacitet att kasta ljus över centrala samhällsfrågor. Forskning om barn bör inte bara vara en forskning om en viss grupp i samhället. Den nyare bamdomsforskningen söker tillämpa ett bamperspektiv. Detta innebär att fenomen studeras såsom de framstår från barnens perspektiv och att inverkan av olika sociala reformer, politiska förändringar och produktion av varor på barns liv belyses. Det handlar alltså både om att söka efter barnens perspektiv och att söka efter konsekvenserna för barnen av olika samhälleliga förändringar. Nya fålt som t.ex. barndomshistoria, barndomssociologi och barndomsantropologi har uppstått och begreppet generation har införts för att markera vikten av att anlägga ett generationsperspektiv på frågor som vanligtvis grupperats på annat sätt

Experimental hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension, and altered myocardial function

The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Previously, we reported that juvenile offspring of obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis that neonatal exposure to raised leptin in the immediate postnatal period plays a causal role. Pups from lean Sprague-Dawley rats were treated either with leptin (3 mg/kg IP) or with saline twice daily from postnatal day 9 to 15 to mimic the exaggerated postnatal leptin surge observed in offspring of obese dams. Cardiovascular function was assessed by radiotelemetry at 30 days, and 2 and 12 months. In juvenile (30 days) leptin-treated rats, hearts were heavier and night-time (active period) systolic blood pressure was raised (mm Hg; mean±SEM: male leptin-treated, 132±1 versus saline-treated, 119±1, n=6, P<0.05; female leptin-treated, 132±2 versus saline-treated, 119±1, n=6, P<0.01), and the pressor response to restraint stress and leptin challenge increased compared with saline-treated rats. Heart rate variability demonstrated an increased low:high frequency ratio in 30-day leptin-treated animals, indicative of heightened sympathetic efferent tone. Echocardiography showed altered left ventricular structure and systolic function in 30-day female leptin versus saline-treated rats. These disorders persisted to adulthood. In isolated hearts, contractile function was impaired at 5 months in male leptin-treated rats. Exogenously imposed hyperleptinemia in neonatal rats permanently influences blood pressure and cardiac structure and function

Effects of prenatal IL-6 exposure and hyperinsulinemia on neuroendocrine regulation

Prenatal exposure to infection is associated with several neuroendocrine disorders. We therefore wanted to elucidate if cytokines, generated in response to maternal infection, play a key mechanistic role in this associations. The aim of this study was to examine the effect of prenatal IL-6 exposure, early and late of pregnancy, on blood pressure regulation, and renal and cognitive function in the adult offspring. Prenatal IL-6 exposure led to hypertension, in females at 5 wk of age, and males at 11 wk of age, dysregulation of the HPA-axis and the RAS system (in females), and altered renal fluid and electrolyte excretion. We also found neuron loss in the hippocampus with decreased learning performance in the morris water maze. These findings suggest that fetal IL-6 exposure reprograms the HPA-axis and RAS system, which results in hypertension and impaired learning ability at adult age. To conclude, these results show that prenatal IL-6 exposure can induce gender specific programming of neuroendocrine regulation with consequences in adult life.Hyperinsulinemi has been associated with left ventricle hypertrophy (LVH). Thus, theobjectives of this study were to investigate the effects of hyperinsulinemia on cardiac structure, function and gene expression, with control of counter-regulatory factors by adrenalectomy (ADX) and â-antagonist metoprolol (MET) treatment. Furthermore we wanted to investigate the effects on insulin signaling phosphatidylinositol 3 kinase (PI3K), and growth promoting- mitogen-activated protein kinases (MAPKs) pathways.Echocardiography performed after insulin treatment revealed LVH, with altered cardiac function (decreased cardiac output). Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Insulin also increased the activity of several regulatory genes important for growth, involved in adrenergic, angiotensin II, and the MAPK pathways. The insulin signaling pathway (PI3K) was on the other hand unaffected. In conclusion, our findings suggest that insulin has a direct trophic effect on the heart, via the MAPK pathway. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV functio

Sucrose feeding in mouse pregnancy leads to hypertension, and sex-linked obesity and insulin resistance in female offspring

Eating an unbalanced diet during pregnancy may induce long-term health consequences in offspring, in particular obesity, insulin resistance and hypertension. We tested the hypothesis that a maternal diet rich in simple sugars predispose mouse offspring to obesity, glucose intolerance and cardiovascular diseases in adulthood.Female C57BL/6J mice were fed either a standard chow or a sucrose-rich diet (26% of total energy) 6 weeks prior to mating, throughout pregnancy and lactation. Offspring of control dams (OC) and high sucrose fed dams (OSF) were weaned onto standard control chow, and metabolic and cardiovascular parameters determined at 3 months of age. Both male and female OSF were hyperphagic by 4 weeks of age and females were heavier than OC at 9 weeks. At 3 months, female OSF showed a significant increase in inguinal fat pad mass, whereas skeletal muscle mass (tibialis anterior) and locomotor activity were decreased relative to OC. A ten-fold increase in fasting serum insulin in female OSF versus OC at 3 months (Insulin [pmol/L] mean±SEM, OSF, 200.3±16.1, versus OC, 20.3±1.8, n=6 P<0.001), was associated with impaired glucose tolerance (AUC [mmol/L min] mean±SEM, OSF 1437.4±124.2 versus OC, 1076.8±83.9, n=6, P<0.05). Both male and female OSF were hypertensive as assessed by radiotelemetry (night-time systolic arterial pressure [mmHg] mean±SEM, male OSF, 128±1 versus OC, 109±1, n=6, P<0.01; female OSF, 130±1 versus OC, 118±1, n=6, P<0.05). Analysis of heart rate variability demonstrated an increased low:high frequency ratio in male and female OSF (P<0.05), indicative of heightened sympathetic efferent tone. Renal tissue noradrenaline content was markely raised in the OSF versus OC (noradrenaline [pg/ml/mg tissue] mean±SEM, male OSF, 2.28±0.19 versus OC 0.84±0.09, n=6, P<0.01) . Exposure to a maternal diet rich in sucrose led to obesity and glucose intolerance in female mice offspring, and hypertension in both sexes